Project Summary The number of people living with diabetes mellitus (DM) worldwide is expected to increase significantly the coming decade. Currently, more than 8% of the population in the United States has DM. Diabetes is the most common cause of renal insufficiency and failure called diabetic kidney disease (DKD). As a result, nearly 180,000 people are living with DKD in the US. Cardiovascular complications are the leading cause of death in patients with DM and DKD. Vascular calcification, a predictor of morbidity and mortality, is commonly associated with these pathologies and is the result of metabolic insults also inherent to dyslipidemia, hypertension and aging. ABCC6 deficiency is the primary cause for chronic and acute forms of cardiovascular calcification described in the human diseases pseudoxanthoma elasticum (PXE), ?-thalassemia, certain cases of generalized arterial calcification of infancy (GACI) and dystrophic cardiac calcification in mice. These diseases are providing clues to a better understanding of pathological calcification in diabetes and DKD. Indeed, multiple lines of evidence now suggest that ABCC6 is an important determinant of vascular calcification in DM and kidney disease. ABCC6 is membrane transporter primarily found in liver and kidneys and exports unknown substrates that mediate the cellular efflux of inorganic pyrophosphate (PPi), a potent calcification inhibitor. As ABCC6 deficiency is also associated with altered cholesterols levels and atherosclerosis, we hypothesize that ABCC6 deficiency in liver and kidneys causes an imbalance of circulating calcification inhibitors (including PPi) enhancing medial calcification in DM and DKD and dyslipidemia. To test this hypothesis, we propose in related specific aims to determine how ABCC6 influences calcification of the vasculature in a diabetic and DKD conditions with mouse models of DM and DKD. We will also determine how ABCC6 deficiency lead to dyslipidemia and atherosclerosis using isolated macrophages and animal models. We expect that the experiments proposed in this application will elucidate the role of ABCC6 in the homeostasis cardiovascular tissues, which may lead to the development of new prognostic indicators and treatment of diabetes-related cardiovascular maladies.